JP7460521B2 - Method for the synthesis of cyclodextrin derivatives - Google Patents

Description

The present invention relates to an improved method for the synthesis of 6-per-deoxy-6-per-(2-carboxyethyl)thio-γ-cyclodextrin or a salt thereof.

Sugammadex is the internationally accepted non-proprietary name (INN) of 6-per-deoxy-6-per-(2-carboxyethyl)thio-γ-cyclodextrin, which has an empirical formula of C ₇₂ H ₁₁₂ O ₄₈ S ₈ and a molecular weight of 2002.18 g/mol.

The octa-sodium salt of sugammadex (Compound I) (hereinafter referred to as sugammadex sodium) is known to be therapeutically useful in reversing neuromuscular blockade induced by rocuronium or vecuronium. In Europe and the United States, sugammadex sodium is sold under the name Bridion™.

Sugammadex was first described in US Patent RE 44,733. Specifically, Example 4 of the patent discloses the reaction of 3-mercaptopropionic acid with 6-per-deoxy-6-peri-iodo-γ-cyclodextrin in the presence of sodium hydride using dry N,N-dimethylformamide as the solvent. After work-up, sugammadex sodium was isolated in 43% yield. The preparation of 6-per-deoxy-6-peri-iodo-γ-cyclodextrin is disclosed in Example 3 of the patent and involves the reaction of γ-cyclodextrin with iodine in the presence of triphenylphosphine (PPh ₃ ) and N,N-dimethylformamide. This process involves the production of triphenylphosphine oxide as a by-product. The removal of triphenylphosphine oxide is very difficult because it is easily soluble in most organic solvents and is very difficult to separate from the final product, necessitating repeated washing with water and acetone, leading to variable yields of the final product.

Example 2 of U.S. Pat. No. 9,120,876 describes the preparation of 6-per-deoxy-6-per-chloro-γ-cyclodextrin in the presence of sodium hydride in N,N-dimethylformamide as a solvent. The preparation of sugammadex sodium by reaction with mercaptopropionic acid is disclosed. Chromatographic purification is described to obtain pure sugammadex sodium (60% yield). In this case, the preparation of the intermediate 6-per-deoxy-6-per-chloro-γ-cyclodextrin involves the use of phosphorus pentachloride and N,N-dimethylformamide (see Example 1). The use of phosphorus pentachloride is undesirable due to its toxicity.

These two processes involve the use of sodium hydride and chromatographic purification of sugammadex sodium, both of which are inconvenient for industrial operation. Sodium hydride is difficult to handle, as it ignites in air and releases hydrogen, especially on contact with water, which is also highly flammable. Therefore, in practice, sodium hydride is supplied as an oil dispersion, usually a mixture of 60% sodium hydride (w/w) in mineral oil. The use of this oil dispersion complicates the workup of the process after the reaction is complete.

Example 2 of WO 2014/125501 A1 discloses the reaction of 6-per-deoxy-6-per-chloro-γ-cyclodextrin with 3-mercaptopropionic acid in the presence of sodium methoxide in N,N-dimethylformamide to obtain crude sugammadex sodium. Instead of purifying this crude material by chromatography, it is treated with activated carbon (20% w/w) and crystallized from a mixture of water and methanol. Even though sodium methoxide is easier to handle than sodium hydride, it requires special care and attention in its handling, since it is highly corrosive and prone to hydrolysis. Moreover, the use of large amounts of activated carbon is undesirable on an industrial scale for environmental reasons, since a large amount of saturated carbon is generated as a residue.

Example 4 of WO 2016/194001 A1 discloses the reaction of 6-per-deoxy-6-per-chloro-γ-cyclodextrin with 3-mercaptopropionic acid in the presence of sodium amide in N,N-dimethylformamide to obtain crude sugammadex sodium. The crude material is purified by a preparative HPLC method. Example 5 of WO 2016/194001 A1 discloses the reaction of 6-per-deoxy-6-per-chloro-γ-cyclodextrin with 3-mercaptopropionic acid in the presence of sodium amide in N,N-dimethylformamide to obtain crude sugammadex sodium. The crude material is treated with charcoal and crystallized from a mixture of water and methanol. Example 6 of WO 2016/194001 A1 discloses the reaction of 6-per-deoxy-6-per-chloro-γ-cyclodextrin with 3-mercaptopropionic acid in the presence of sodium hydroxide in N,N-dimethylformamide to obtain crude sugammadex sodium. The crude material is treated with activated carbon in water and recrystallized from a mixture of methanol and water. In this case, the intermediate 6-per-deoxy-6-per-chloro-γ-cyclodextrin is produced by reacting γ-cyclodextrin with phosgene (see Example 1) or oxalyl chloride (see Examples 2 and 3). WO 2016/194001 A1 teaches that a preparative HPLC method is required to obtain higher purity sugammadex sodium according to the method disclosed in this patent application. This preparative HPLC method would not be applicable on an industrial scale.

China Patent Application Publication No. 106749771A discloses that the intermediate 6-per-deoxy-6-per-bromo-γ-cyclodextrin is synthesized with sodium hydroxide, sodium tert-butoxide in N,N-dimethylformamide as a solvent. , discloses several preparations of sugammadex sodium by reacting with 3-mercaptopropionic acid in the presence of a base such as sodium carbonate, sodium bicarbonate, or sodium methoxide. Example 1 of Chinese Patent Application Publication No. 106749771A discloses that the intermediate 6-per-deoxy-6-per-iodo-γ-cyclodextrin was prepared in a solution of sodium hydroxide in N,N-dimethylformamide as a solvent. Discloses the preparation of sugammadex sodium by reacting with 3-mercaptopropionic acid in the presence of 3-mercaptopropionic acid. The yield provided is between 62% and 83%. The purity of the obtained crude sugammadex sodium is not stated.

Examples 5 to 10 of WO 2017/084401A1 describe the preparation of 6-per-deoxy-6-per-iodo-γ-cyclo in the presence of sodium hydride using dry N,N-dimethylformamide as the solvent. Discloses the preparation of sugammadex sodium by reacting dextrin and 3-mercaptopropionic acid. In Examples 11-21, crude sugammadex sodium is treated with a large amount of charcoal and/or alumina, ie at least 20% w/w, and recrystallized from a mixture of water and methanol or ethanol.

Example 7 of WO 2017/089966A1 describes the preparation of 6-per-deoxy-6-per-chloro-γ-cyclodextrin and 3-mercaptopropion in the presence of sodium tert-butoxide using dimethyl sulfoxide as a solvent. Discloses the preparation of sugammadex sodium by reacting acids. Crude sugammadex sodium is purified by ultrafiltration, which is an inconvenient purification technique on an industrial scale. Example 8 of WO 2017/089966A1 describes the reaction between 6-per-deoxy-6-per-chloro-γ-cyclodextrin and 3 in the presence of sodium hydride using N,N-dimethylformamide as a solvent. - Discloses the preparation of sugammadex sodium by reacting mercaptopropionic acid. Crude sugammadex sodium is purified by size exclusion chromatography on silica gel using a Sephadex G-25 column. Both purification methods used are inconvenient on an industrial scale.

WO 2017/144734 A2 discloses the preparation of sugammadex sodium by reacting 6-per-deoxy-6-per-bromo-γ-cyclodextrin with 3-mercaptopropionic acid in the presence of sodium hydroxide using dimethylsulfoxide as a solvent. Example 3 describes that the obtained sugammadex sodium has a purity of 88.4% (HPLC).

WO 2017/163165A1 discloses the preparation of sugammadex sodium by reacting 6-perdeoxy-6-per-chloro-γ-cyclodextrin with the disodium salt of 3-mercaptopropionic acid in dimethylsulfoxide in the absence of a base. (Examples 4-6). The disodium salt of 3-mercaptopropionic acid is prepared by reacting 3-mercaptopropionic acid with sodium hydroxide in tetrahydrofuran (Example 3). The resulting disodium salt of 3-mercaptopropion is then isolated and further purified by suspension in a mixture of tetrahydrofuran and N,N-dimethylformamide (Example 3). The resulting disodium salt of 3-mercaptopropionic acid has a purity of 97% in HPLC area %. WO 2017/163165A1 discloses that during the substitution reaction of 6-per-deoxy-6-per-halo-γ-cyclodextrin with 3-mercaptopropionic acid, if excess base is present, it is difficult to remove it from the reaction mixture. It is described that it generates unnecessary impurities that are extremely difficult to handle. Example 6 produced sugammadex sodium with a purity of 98.0% by HPLC area % by reacting 6-perdeoxy-6-per-chloro-γ-cyclodextrin with the disodium salt of 3-mercaptopropionic acid. discloses the preparation of Crude sugammadex sodium is treated with activated carbon in water. The final sugammadex sodium is obtained by lyophilization. Yield is approximately 40%.

WO 2018/136013 A1 discloses the preparation of sugammadex sodium by reacting 6-per-deoxy-6-per-chloro-γ-cyclodextrin with 3-mercaptopropionic acid in the presence of sodium hydroxide (Examples 2-3), sodium tert-butoxide (Example 4) or sodium methoxide (Example 5). WO 2018/136013 A1 discloses a method for purifying crude sugammadex sodium, which comprises converting sugammadex sodium to sugammadexic acid (Example 6) and then purifying by RP-18 silica gel or activated carbon (Example 7). The sugammadexic acid is then converted to purified sugammadex sodium (Example 8). The purity for the final purified sugammadex sodium is not described.

WO 2018/185784A1 discloses that 6-per-deoxy-6-per-chloro-γ-cyclodextrin and 3-cyclodextrin in the presence of sodium methoxide in methanol using N,N-dimethylformamide as a solvent. Discloses the preparation of sugammadex sodium by reacting mercaptopropionic acid (Example 3). WO 2018/185784A1 also describes the purification of crude sugammadex sodium comprising converting sugammadex sodium to sugammadex acid and purifying it by preparative HPLC and further lyophilization of sugammadex sodium to obtain the final sugammadex sodium. A multi-step method is disclosed. Preparative HPLC and lyophilization are not efficient methods to be carried out on an industrial scale.

None of the methods disclosed in the prior art involve the preparation and isolation of the mono-salt of 3-mercaptopropionic acid with an alkali metal.

The European Medicines Agency's (EMA) Public Medicines Review Report for Bridion™ states that the synthesis of sugammadex requires complete conversion of eight identical functional groups per molecule, resulting in structural changes to γ-cyclodextrin. It has been described that the process is complicated by the occurrence of high levels of impurities that are associated with and therefore very difficult to remove.

Specifically, the U.S. Food and Drug Administration (FDA) Chemical Review Data Sheet states that Bridion™ may contain up to 7% of a mono-OH derivative of sugammadex sodium called Org48302.

Therefore, there is a need to provide an improved industrially applicable process for preparing sugammadex or a pharma- ceutically acceptable salt thereof, preferably sugammadex sodium, in high yield and high purity.

FIG. 1 shows the powder X-ray diffractogram (XRPD) of 6-per-deoxy-6-per-chloro-γ-cyclodextrin (compound II-A) obtained according to Example 1. FIG. 2 shows the powder X-ray diffractogram (XRPD) of the monosodium salt of 3-mercaptopropionic acid (compound IV-A) obtained according to Example 4. FIG. 3 shows the powder X-ray diffractogram (XRPD) of Sugammadex sodium (Compound I) obtained according to Example 7. Figure 4 shows the monosodium salt of 3-mercaptopropionic acid (compound IV-A) and the di-sodium salt of 3-mercaptopropionic acid during the hydration process at 80 ± 2% relative humidity (RH) and 25 °C immediately after drying. The weight increase rate of the sodium salt (compound VA) is shown.

The aim of the present invention is to overcome the drawbacks of the methods disclosed in the prior art and make it possible to obtain sugammadex or a pharmaceutically acceptable salt thereof, preferably sugammadex sodium, in higher purity and in higher yields. An object of the present invention is to provide an improved method for the preparation of sugammadex or a pharmaceutically acceptable salt thereof, preferably sugammadex sodium, on a commercial scale.

The process of the present invention provides high yield and high purity sugammadex or a pharma- ceutically acceptable salt thereof, preferably sugammadex sodium, without the need for purification procedures that are inconvenient on an industrial scale.

イオン性塩基と反応させて、式（ＩＶ）のモノ塩を得る工程と、

（式中、Ｍはアルカリ金属である）
ｂ）式（ＩＶ）のモノ塩を単離する工程と、
ｃ）イオン性塩基の存在下で、式（ＩＶ）のモノ塩を式（ＩＩ）の化合物またはその水和物もしくは溶媒和物と反応させる工程と

（式中、ＸはＣｌ、Ｂｒ、Ｉ、またはＯＳＯ_２Ｒであり、Ｒは、場合によりＦ、Ｃｌ、ＢｒまたはＩで置換されていてもよいＣ_１～Ｃ_４アルキル、フェニルまたはＣ_１～Ｃ_４アルキルフェニルである）
を含む、スガマデクスまたはその塩、好ましくはスガマデクスナトリウムの調製方法を提供する。 The first aspect of the present invention is a method for producing a cellular membrane comprising the steps of:
a) reacting 3-mercaptopropionic acid of formula (III) with

with an ionic base to obtain the mono-salt of formula (IV);

(wherein M is an alkali metal)
b) isolating the mono-salt of formula (IV);
c) reacting the monosalt of formula (IV) with a compound of formula (II) or a hydrate or solvate thereof in the presence of an ionic base;

wherein X is Cl, Br, I, or OSO ₂ R, and R is C ₁ -C ₄ alkyl, phenyl, or C ₁ -C ₄ alkylphenyl, optionally substituted with F, Cl, Br, or I.
The present invention provides a method for preparing sugammadex or a salt thereof, preferably sugammadex sodium, comprising:

The authors of the present invention have found that using the isolated monosalt of formula (IV), sugammadex or a salt thereof, preferably sugammadex sodium, can be obtained in better yield and higher purity. This method gives high purity sugammadex or a salt thereof, preferably sugammadex sodium, in high yield, without the need for purification methods which are inconvenient on an industrial scale.

The reaction of the 3-mercaptopropionic acid of formula (III) with the ionic base of step a) is preferably carried out in an organic solvent. The organic solvent used may be selected from the group consisting of polar aprotic solvents such as dimethylsulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide, etc.; alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, etc.; hydrocarbon solvents such as benzene, toluene, xylene, heptane, hexane, and cyclohexane; ether solvents such as di-tert-butyl ether, diethyl ether, diisopropyl ether, 1,4-dioxane, methyl tert-butyl ether, ethyl tert-butyl ether, tetrahydrofuran, and dimethoxyethane, and mixtures thereof. Preferably, the reaction of 3-mercaptopropionic acid of formula (III) with the ionic base of step a) is carried out in an alcoholic solvent, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or mixtures thereof, more preferably in isopropanol.

As used herein, the term "ionic base" refers to an ionic compound containing an alkali metal cation and a suitable basic anion.

The basic anion used in step a) of the process of the invention can be selected from the list comprising amides, hydrides, alkoxides, hydroxides and mixtures thereof.

Preferably, the ionic base used in step a) of the method of the present invention is an alkaline ionic base, such as a sodium, potassium, lithium or cesium ionic base, more preferably a sodium ionic base.

The sodium ionic base used in step a) of the process of the invention is preferably selected from the group comprising sodium amide, sodium hydride, sodium alkoxide, sodium hydroxide and/or mixtures thereof. . More preferably, the ionic base used in step a) is sodium hydroxide. The sodium hydroxide used in step a) may be in solid form or in solution. Preferably, sodium hydroxide is used in solid form.

The monosalts of formula (IV) of the present invention also include any hydrates or solvates thereof. Preferably, the monosalt of formula (IV) according to the invention is in non-hydrated form.

The monosalt of formula (IV) is preferably the monosodium salt of 3-mercaptopropionic acid, a compound of formula (IV-A).

The authors of the present invention have found that the monosalt of formula (IV), preferably the monosodium salt of formula (IV-A), once isolated, can be used directly for the preparation of sugammadex sodium without the need for further purification methods.

The use of an isolated salt of 3-mercaptopropionic acid allows the starting material 3-mercaptopropionic acid to be purified before its use in the preparation of sugammadex or its salt, preferably sugammadex sodium.

式中、Ｍはアルカリ金属である。 The authors of the present invention have surprisingly found that the isolation of the monosalt of formula (IV), preferably the monosodium salt of formula (IV-A), is better than that of the corresponding di-salt (formula V). It has been found that purification of 3-mercaptopropionic acid is involved.

In the formula, M is an alkali metal.

The authors of the present invention believe that the monosodium salt of formula (IV-A) is less hygroscopic and more stable than the disodium salt of formula (VA). It has been found that the sodium salt is easier to handle than the corresponding disodium salt of formula (VA). For example, the monosodium salt of formula (IV-A) can be stored for a longer period of time without requiring special storage conditions before being used in the preparation of sugammadex sodium, whereas the disodium salt of formula (VA) , requires more care in view of higher hygroscopicity and lower stability.

Very high hygroscopicity can cause deliquescence, which involves the material absorbing enough water to form an aqueous solution, which is highly undesirable for a product that must be handled and/or stored prior to its use. At the same time, the more hygroscopic a material is, the more difficult it is to keep dry prior to its use.

Furthermore, when a salt with low hygroscopicity such as the monosodium salt of formula (IV-A) is used, the monosodium salt of formula (IV-A) and the compound of formula (II) or a hydrate or solvate thereof may be used. The presence of undesirable water in the reaction is reduced. The presence of excess water in this reaction is detrimental to the quality of the final sugammadex or its salt, preferably sugammadex sodium, as the presence of water can lead to various hydrolyzed impurities such as Org48302. This is because of their gender.

The ionic base, preferably sodium ionic base, more preferably sodium hydroxide in solid form, in step a) of the process of the invention is preferably 0.5 It is used in a molar ratio of ˜1, more preferably in a molar ratio of 0.9 to 1.0, even more preferably in a molar ratio of 0.95.

Preferably, the reaction of the 3-mercaptopropionic acid of formula (III) with an ionic base, preferably a sodium ionic base, more preferably sodium hydroxide in solid form, in step a) is carried out at a temperature between 0° C. and 50° C. It is more preferably carried out at a temperature of 20°C to 30°C, even more preferably 20°C to 25°C.

Isolation of the monosalt of formula (IV), preferably the monosodium salt of formula (IV-A), is preferably carried out by filtration from the reaction mixture. Preferably, a hydrocarbon solvent, more preferably heptane, is added before filtration of the reaction mixture to isolate the monosalt of formula (IV), preferably the monosodium salt of formula (IV-A).

The mono salt of formula (IV), preferably the mono sodium salt of formula (IV-A), of the present invention is greater than 97% (% area) pure when analyzed by HPLC for chromatographic purity, preferably greater than 97.5% (% area) pure when analyzed by HPLC for chromatographic purity, more preferably greater than 98.0% (% area) pure when analyzed by HPLC for chromatographic purity, and even more preferably greater than 98.5% (% area) pure when analyzed by HPLC for chromatographic purity.

In step c), a monosalt of formula (IV), preferably a monosodium salt of formula (IV-A), and a compound of formula (II) or a hydrate or solvate thereof in the presence of an ionic base; The reaction is preferably carried out in an organic solvent. The organic solvents used are polar aprotic solvents, such as dimethylsulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide, etc.; alcoholic solvents, such as methanol, ethanol, n-propanol, isopropanol, n- butanol etc.; hydrocarbon solvents such as benzene, toluene, xylene, heptane, hexane, and cyclohexane; ether solvents such as di-tert-butyl ether, diethyl ether, diisopropyl ether, 1,4-dioxane, methyl tert-butyl ether , ethyl tert-butyl ether, tetrahydrofuran and dimethoxyethane, and mixtures thereof. Preferably, in step c), a monosalt of formula (IV), preferably a monosodium salt of formula (IV-A) and a compound of formula (II) or a hydrate or solvent thereof in the presence of an ionic base The reaction with the compound is preferably carried out using a polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide, etc., and an alcoholic solvent such as methanol, ethanol, n-propanol, isopropanol. , n-butanol, etc., more preferably in a mixture of N,N-dimethylformamide and methanol.

The basic anion used in step c) of the process of the present invention can be selected from the list including amides, hydrides, alkoxides, hydroxides and mixtures thereof.

Preferably, the ionic base used in step c) of the process of the invention is an alkaline ionic base, such as a sodium, potassium, lithium or cesium ionic base, more preferably a sodium ionic base.

The sodium ionic base used in step c) is preferably selected from the group comprising sodium amide, sodium hydride, sodium alkoxide, sodium hydroxide and/or mixtures thereof. More preferably, the ionic base used in step c) is sodium hydroxide. The sodium hydroxide used in step c) may be in solid form or in solution. Preferably, sodium hydroxide is used in solid form to avoid the presence of excess moisture in the reaction medium.

The ionic base, preferably sodium ionic base, more preferably sodium hydroxide in solid form, in step c) of the process of the invention is preferably a monosalt of formula (IV), preferably a monosalt of formula (IV-A) It is used in a molar ratio of 0.5 to 1, preferably in a molar ratio of 1, relative to the monosodium salt of .

In step c), the reaction of the monosalt of formula (IV), preferably the monosodium salt of formula (IV-A), with the compound of formula (II) or a hydrate or solvate thereof in the presence of an ionic base, preferably a sodium ionic base, more preferably sodium hydroxide in solid form, is carried out at a temperature of 20°C to 160°C, preferably 60°C to 130°C, more preferably 90°C to 120°C, even more preferably 95°C to 110°C.

In step c), a monosalt of formula (IV), preferably monosodium of formula (IV-A), in the presence of an ionic base, preferably a sodium ionic base, more preferably sodium hydroxide in solid form. The reaction of the salt with the compound of formula (II) or its hydrate or solvate is carried out at 95°C to 100°C for 4 to 8 hours, preferably about 6 hours, followed by 8 to 12 hours at 105°C to 110°C. , preferably for about 10 hours.

Preferably, all the methods of the present invention, i.e. steps a), b) and c), are carried out in the presence of an inert atmosphere. The inert atmosphere can be provided by providing a vacuum or an inert gas. The inert gas can be nitrogen or argon, preferably nitrogen.

またはその水和物もしくは溶媒和物
である。 The compound of formula (II) or a hydrate or solvate thereof is preferably selected from the group consisting of 6-per-deoxy-6-per-chloro-γ-cyclodextrin, 6-per-deoxy-6-per-bromo-γ-cyclodextrin, and 6-per-deoxy-6-peri-iodo-γ-cyclodextrin, or a hydrate or solvate thereof. More preferably, the compound of formula (II) or a hydrate or solvate thereof is 6-per-deoxy-6-per-chloro-γ-cyclodextrin, which is a compound of formula (II-A).

or a hydrate or solvate thereof.

In a preferred embodiment, the compound of formula (II) wherein X is Cl, Br, I, or a hydrate or solvate thereof is preferably
a) reacting a sulfonyl halide with a tertiary amide compound to form a Vilsmeier reagent;
b) reacting Vilsmeier reagent with γ-cyclodextrin.

γ-Cyclodextrins are commercially available or can be synthesized according to the teachings of the prior art.

The γ-cyclodextrin used in the method of the invention is preferably dry γ-cyclodextrin, more preferably less than 5% water by weight, more preferably less than 2% water, more preferably 1% water by weight. Dry γ-cyclodextrin containing less than 0.5% water, most preferably less than 0.5% water by weight. For example, γ-cyclodextrin can be dried in a vacuum oven, optionally heated.

In a particularly preferred embodiment of the invention, X is Cl and the sulfonyl halide is sulfonyl chloride. Preferably, the sulfonyl chloride of step a) used to prepare the compound of formula (II-A) or a hydrate or solvate thereof is methanesulfonyl chloride, ethanesulfonyl chloride, allylsulfonyl chloride, 1- Propanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, 4-ethylbenzenesulfonyl chloride, m-xylene-4-sulfonyl chloride, p-xylene-2-sulfonyl chloride, 4-dodecylbenzenesulfonyl chloride, 2-mesitylenesulfonyl chloride, 2 , 3,5-trichlorobenzenesulfonyl chloride, 2,4-dinitrobenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, heptadecafluorooctanesulfonyl chloride, 1-naphthalenesulfonyl chloride, 2-naphthalenesulfonyl chloride , 1,3,6-naphthalene trisulfonyl chloride, 2,6-naphthalenedisulfonyl chloride, 1,5-naphthalenedisulfonyl chloride, 1-pyrenesulfonyl chloride, and/or mixtures thereof. More preferably the sulfonyl chloride is methanesulfonyl chloride.

In another preferred embodiment of the invention, the tertiary amide compound of step a) comprises N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, and/or mixtures thereof. selected from the group containing. More preferably, the tertiary amide compound is N,N-dimethylformamide.

式中、Ｘは上記に開示されているようにＣｌ、ＢｒまたはＩであり、Ｒはハロゲン化スルホニル試薬（ＲＳＯ_２Ｘ）のアルキルまたはアリール基に対応し、Ｗ、ＹおよびＺは第三級アミド化合物（ＷＣ（Ｏ）ＮＹＺ）の異なる置換基に対応する。好ましくは、Ｘは塩素であり、Ｗは水素であり、Ｒ、ＹおよびＺはメチルであり、その結果、式（ＶＩ）の化合物はＮ－メチル－Ｎ－｛［（メチルスルホニル）オキシ］メチリデン｝メタンアミニウムクロリド（化合物ＶＩ－Ａ）である。

The Vilsmeier reagent formed in the process for preparing the compound of formula (II) of the present invention or a hydrate or solvate thereof (X is Cl, Br, I) corresponds to the compound of formula (VI):

wherein X is Cl, Br or I as disclosed above, R corresponds to the alkyl or aryl group of the sulfonyl halide reagent (RSO ₂ X), and W, Y and Z correspond to the different substituents of the tertiary amide compound (WC(O)NYZ). Preferably, X is chlorine, W is hydrogen, R, Y and Z are methyl, such that the compound of formula (VI) is N-methyl-N-{[(methylsulfonyl)oxy]methylidene}methanaminium chloride (compound VI-A).

The Vilsmeier reagent formed can be isolated or reacted directly with γ-cyclodextrin without an isolation step.

In a preferred embodiment of the present invention, a sulfonyl halide is added to a mixture containing γ-cyclodextrin and a tertiary amide compound.

In a preferred embodiment of the invention, methanesulfonyl chloride is added to a solution of γ-cyclodextrin with N,N-dimethylformamide also acting as a solvent.

Optionally, the preparation of a compound of formula (II) or a hydrate or solvate thereof (wherein Cyclohexane, cumene, 1,2-dichloroethane, 1,2-dichloroethene, dichloromethane, 1,1-diethoxypropane, 1,2-dimethoxyethane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, dimethyl sulfoxide , 1,4-dioxane, ethyl acetate, ethyl ether, ethyl formate, heptane, hexane, isobutyl acetate, isopropyl acetate, isooctane, isopropyl ether, methyl acetate, methyl butyl ketone, methylcyclohexane, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl A solvent selected from the group comprising ketones, nitromethane, pentane, petroleum ether, propyl acetate, pyridine, sulfolane, tetrahydrofuran, 2-methyltetrahydrofuran, tetralin, toluene, 1,1,2-trichloroethene, xylene, and mixtures thereof. is executed in the presence of The tertiary amides that can be used in step a), N,N-dimethylformamide, N,N-dimethylacetamide and N-methyl-2-pyrrolidone, can also act as solvents, in which case there is no need to use an additional solvent. do not have.

Preferably, the reaction of Vilsmeier reagent and γ-cyclodextrin in step b) is carried out in the presence of a halogenated salt. The halogenated salt may be any inorganic salt or any organic salt containing a halogenated anion. Preferably the halide salt is a chloride salt. More specifically, the chloride salt may be selected from the group comprising lithium chloride, sodium chloride, potassium chloride, cesium chloride, magnesium chloride, calcium chloride, quaternary ammonium chloride, and/or mixtures thereof. . In the most preferred embodiment, the chloride salt is lithium chloride.

In another preferred embodiment of the present invention, the reaction of the sulfonyl halide with the tertiary amide compound to form the Vilsmeier reagent is carried out at a temperature of 50°C to 80°C, preferably at a temperature of 60°C to 70°C.

In a preferred embodiment of the invention, the combination of methanesulfonyl chloride and N,N-dimethylformamide to obtain N-methyl-N-{[(methylsulfonyl)oxy]methylidene}methanaminium chloride (compound VI-A) The reaction is carried out at a temperature of 50°C to 80°C, preferably 60°C to 70°C.

In another preferred embodiment of the present invention, the reaction of the Vilsmeier reagent with γ-cyclodextrin is carried out at a temperature between 50°C and 80°C, preferably between 60°C and 70°C.

In a particularly preferred embodiment of the present invention, the reaction of N-methyl-N-{[(methylsulfonyl)oxy]methylidene}methanaminium chloride (compound VI-A) with γ-cyclodextrin is carried out at a temperature of 50°C to 80°C, preferably 60°C to 70°C.

（式中、ＸはＣｌ、Ｂｒ、Ｉである）
ａ）ハロゲン化スルホニルを第三級アミド化合物と反応させてビルスマイヤー試薬を形成する工程と；
ｂ）ビルスマイヤー試薬をγ－シクロデキストリンと反応させる工程と
を含み、工程ｂ）は、ハロゲン化塩の存在下で行われる、方法を提供する。 Another aspect of the present invention is a process for preparing a compound of formula (II) or a hydrate or solvate thereof, comprising the steps of:

(Wherein, X is Cl, Br, I)
a) reacting a sulfonyl halide with a tertiary amide compound to form a Vilsmeier reagent;
and b) reacting the Vilsmeier reagent with γ-cyclodextrin, wherein step b) is carried out in the presence of a halide salt.

The Vilsmeier reagent formed can be isolated or reacted directly with γ-cyclodextrin without an isolation step.

In a preferred embodiment of the invention, the sulfonyl halide is added to a mixture comprising γ-cyclodextrin, tertiary amide compound and halide salt.

In a particularly preferred embodiment, X is Cl, the sulfonyl halide is a sulfonyl chloride, and the halide salt is a chloride salt, so that the compound of formula (II-A) is 6-per-deoxy- 6-per-chloro-γ-cyclodextrin or a hydrate or solvate thereof is obtained.

Preferably, the sulfonyl chloride of step a) used to prepare the compound of formula (II-A) or a hydrate or solvate thereof is methanesulfonyl chloride, ethanesulfonyl chloride, allylsulfonyl chloride, 1- Propanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, 4-ethylbenzenesulfonyl chloride, m-xylene-4-sulfonyl chloride, p-xylene-2-sulfonyl chloride, 4-dodecylbenzenesulfonyl chloride, 2-mesitylenesulfonyl chloride, 2 , 3,5-trichlorobenzenesulfonyl chloride, 2,4-dinitrobenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, heptadecafluorooctanesulfonyl chloride, 1-naphthalenesulfonyl chloride, 2-naphthalenesulfonyl chloride , 1,3,6-naphthalene trisulfonyl chloride, 2,6-naphthalenedisulfonyl chloride, 1,5-naphthalenedisulfonyl chloride, 1-pyrenesulfonyl chloride, and/or mixtures thereof. More preferably the sulfonyl chloride is methanesulfonyl chloride.

Preferably, the chloride salt in step b) of preparing the compound of formula (II-A) or a hydrate or solvate thereof is lithium chloride, sodium chloride, potassium chloride, cesium chloride, magnesium chloride, calcium chloride, selected from the group comprising quaternary ammonium chloride, and/or mixtures thereof; More preferably the chloride salt is lithium chloride.

Bull. Soc. Chim. Fr. 1995,132,857-866 discloses the preparation of 6-per-deoxy-6-per-chloro-γ-cyclodextrin in 97% yield by reacting γ-cyclodextrin with methanesulfonyl chloride in dry N,N-dimethylformamide at 65°C (compound 2γ). The purity of the resulting 6-per-deoxy-6-per-chloro-γ-cyclodextrin is not reported.

The authors of the present invention have shown that when the reaction between the Vilsmeier reagent and γ-cyclodextrin in step b) is carried out in the presence of a halide salt, preferably a chloride salt, It has been found that both the yield and purity of compounds of formula (II), preferably compounds of formula (II-A), or hydrates or solvates thereof, are increased.

In a preferred embodiment of the invention, methanesulfonyl chloride is added to a solution of γ-cyclodextrin and lithium chloride in N,N-dimethylformamide.

The compound of formula (II), preferably the compound of formula (II-A), or a hydrate or solvate thereof, produced according to the method of the present invention is of higher purity.

Preferably, the tertiary amide compound of step a) for preparing the compound of formula (II) or its hydrate or solvate, where X is Cl, Br, I, is selected from the group comprising N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, and/or mixtures thereof. More preferably, the tertiary amide compound is N,N-dimethylformamide.

In another embodiment of the invention, a compound of formula (II) or a hydrate or solvate thereof, preferably a compound of formula (II-A), 6-per-deoxy-6-per-chloro-γ - Cyclodextrins or hydrates or solvates thereof can be purified by recrystallization or suspension in water, organic solvents or mixtures thereof. A compound of formula (II) or a hydrate or solvate thereof, preferably a compound of formula (II-A), 6-per-deoxy-6-per-chloro-γ-cyclodextrin or a hydrate or The organic solvent used for the purification of the solvate is preferably a polar aprotic solvent, such as dimethylsulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide, etc.; an alcoholic solvent, such as methanol, ethanol , n-propanol, isopropanol, n-butanol, etc.; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone, and mixtures thereof. Preferably, a compound of formula (II) or a hydrate or solvate thereof, preferably a compound of formula (II-A), 6-per-deoxy-6-per-chloro-γ-cyclodextrin or its water The hydrate or solvate can be reconstituted in a mixture of solvents comprising N,N-dimethylformamide, acetone and water, or in a mixture of solvents comprising methanol and water, for example in a mixture of methanol, acetone and water. Purification can be achieved by crystallization or suspension. In a preferred embodiment, a compound of formula (II) or a hydrate or solvate thereof, preferably a compound of formula (II-A), 6-per-deoxy-6-per-chloro-γ-cyclodextrin or Recrystallization or suspension of the hydrate or solvate is carried out at a temperature of -30°C to 80°C, preferably -20°C to 60°C.

Furthermore, the compound of formula (II) or a hydrate or solvate thereof, preferably the compound of formula (II-A), 6-per-deoxy-6-per-chloro-γ-cyclodextrin or a hydrate or solvate thereof, can be purified by recrystallization or suspension in a mixture containing water and an organic solvent as described above, and the pH of the mixture is adjusted to 0.5 to 13.5, preferably 8.0 to 13.0, using aqueous sodium hydroxide or hydrochloric acid.

Furthermore, a compound of formula (II) or a hydrate or solvate thereof, preferably a compound of formula (II-A), 6-per-deoxy-6-per-chloro-γ-cyclodextrin or a hydrate thereof. The product or solvate can be purified by recrystallization or suspension in a mixture containing water and an organic solvent as described above, the pH of the mixture being adjusted to 0 using aqueous sodium hydroxide or hydrochloric acid. It is adjusted to .5 to 13.5, preferably 0.5 to 1.5.

Another aspect of the present invention provides a compound of formula (II) or a hydrate or solvate thereof, wherein X is Cl, Br, I, preferably 6-per-deoxy-6-per-chloro-γ-cyclodextrin (II-A) or a hydrate or solvate thereof obtained according to the method disclosed in the present invention.

Another aspect of the present invention provides a method for preparing sugammadex or a salt thereof, preferably sugammadex sodium, from a compound of formula (II) or a hydrate or solvate thereof, wherein X is Cl, Br, I, preferably 6-per-deoxy-6-per-chloro-γ-cyclodextrin (II-A) or a hydrate or solvate thereof, which is prepared according to the method disclosed in the present invention.

Advantageously, sugammadex or a salt thereof, preferably sugammadex sodium, obtained according to any of the methods of the invention can be purified by recrystallization or suspension in water, organic solvents or mixtures thereof. . The organic solvent used for the purification of sugammadex or its salt, preferably sugammadex sodium, is preferably a polar aprotic solvent, such as dimethyl sulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide, etc.; an alcoholic solvent , such as methanol, ethanol, n-propanol, isopropanol, n-butanol, etc.; hydrocarbon solvents, such as benzene, toluene, xylene, heptane, hexane, and cyclohexane; ethereal solvents, such as di-tert-butyl ether, diethyl ether, diisopropyl ether, 1,4-dioxane, methyl tert-butyl ether, ethyl tert-butyl ether, tetrahydrofuran and dimethoxyethane, and mixtures thereof. Preferably, sugammadex or a salt thereof, preferably sugammadex sodium, is prepared by recrystallization or suspension in a mixture of water and an alcoholic solvent, more preferably with water, methanol and/or ethanol, and optionally heptane. Purified by recrystallization or suspension in a mixture.

If desired, the sugammadex or its salt, preferably sugammadex sodium obtained according to any of the processes of the present invention can be further purified by reacting the obtained sugammadex or its salt, preferably sugammadex sodium with acrylic acid or its salt or ester, preferably methyl acrylate, to reduce the amount of Imp 1200. Upon reacting sugammadex or its salt, preferably sugammadex sodium containing Imp 1200 with an ester of acrylic acid such as methyl acrylate, the obtained sugammadex monoester derivative is further hydrolyzed, preferably under basic conditions, to recover sugammadex or its salt, preferably sugammadex sodium.

The process of the present invention results in highly pure sugammadex or a salt thereof, preferably sugammadex sodium, without the need to use purification techniques that are inconvenient on an industrial scale.

As used herein, the term "purification techniques that are inconvenient on an industrial scale" refers to purification techniques that are different from common operations performed on an industrial scale, such as filtration, extraction, crystallization, recrystallization or suspension. Refers to all refining techniques. Purification techniques such as chromatography, adsorption, dialysis or ultrafiltration are included in the term "purification techniques that are inconvenient on an industrial scale".

Another aspect of the invention provides highly purified sugammadex or a salt thereof, preferably sugammadex sodium.

As used herein, the term "highly pure" means greater than 95% (% area) purity when analyzed by HPLC methods for chromatographic purity, preferably more than 95% (% area) purity when analyzed by HPLC methods for chromatographic purity. more preferably greater than 98.0% (% area) when analyzed by HPLC method for chromatographic purity; even more preferably, greater than 98.0% (% area); It means sugammadex or a salt thereof, preferably sugammadex sodium, which is more than 99.0% (% area) pure when analyzed by HPLC method for purity.

The % area of a particular compound used in the present invention is calculated as follows: the area of the particular compound of the HPLC chromatogram obtained as defined by the HPLC method for chromatographic purity of the present invention is Divide by the sum of all peak areas of the HPLC chromatograms obtained as defined by the HPLC method for chromatographic purity of the invention. Next, multiply the obtained value by 100.

HPLC methods for chromatographic purity according to the present invention include any HPLC method used to determine the purity of sugammadex or a salt thereof, preferably sugammadex sodium. Preferably, the HPLC method for chromatographic purity comprises the HPLC method for chromatographic purity used in the present invention.

The method according to the present invention results in sugammadex or a salt thereof, preferably sugammadex sodium, having a purity of greater than 95% (% area) when analyzed by HPLC method for chromatographic purity, preferably greater than 96.5% (% area) when analyzed by HPLC method for chromatographic purity, more preferably greater than 98.0% (% area) when analyzed by HPLC method for chromatographic purity, and even more preferably greater than 99.0% (% area) when analyzed by HPLC method for chromatographic purity.

Another aspect of the present invention provides sugammadex or a salt thereof, preferably sugammadex sodium, having a purity of greater than 95% (% area) when analyzed by HPLC method for chromatographic purity, preferably greater than 96.5% (% area) when analyzed by HPLC method for chromatographic purity, more preferably greater than 98.0% (% area) when analyzed by HPLC method for chromatographic purity, and even more preferably greater than 99.0% (% area) when analyzed by HPLC method for chromatographic purity.

Another aspect of the present disclosure provides a monosodium salt of 3-mercaptopropionic acid of formula (IV-A). In particular, the present invention provides an isolated monosodium salt of 3-mercaptopropionic acid of formula (IV-A).

Preferably, the isolated monosodium salt of 3-mercaptopropionic acid of formula (IV-A) contains peaks at 2 theta (2θ): 6.1 and 24.9 ± 0.2°, preferably 2 theta (2θ): includes peaks at 6.1, 6.6, 24.9, 27.6, 30.2, 30.7 and 37.7 ± 0.2°, more preferably 2 theta (2θ ): 6.1, 6.6, 9.0, 12.3, 17.9, 18.6, 21.1, 22.8, 24.9, 25.2, 27.6, 28.2, It is characterized by having an X-ray powder diffraction (XRPD) pattern containing peaks at 30.2, 30.7, 37.7 and 46.2±0.2°. In a further aspect of the invention, the monosodium salt of 3-mercaptopropionic acid is characterized by having an X-ray powder diffraction (XRPD) pattern substantially equivalent to the diffraction plot shown in FIG.

Another aspect of the invention provides the use of the monosodium salt of 3-mercaptopropionic acid of formula (IV-A) according to the invention for preparing sugammadex or a salt thereof, preferably sugammadex sodium.

Sugammadex or a salt thereof, preferably sugammadex sodium, obtained according to the method of the invention is used in the preparation of a medicament for the reversal of drug-induced neuromuscular blockade.

Sugammadex or its salts, preferably sugammadex sodium, obtained according to the method of the present invention is preferably administered parenterally. The route of injection may be intravenous, subcutaneous, intradermal, intramuscular, or intra-arterial. The intravenous route is the preferred route. The exact dose used will necessarily depend on the needs of the individual patient to whom the medicine is administered, the degree of muscle activity to be restored, and the judgement of the anesthesiologist/critical care specialist.

Another aspect of the present invention relates to a pharmaceutical composition comprising sugammadex or a salt thereof, preferably sugammadex sodium, obtained according to the method of the present invention. Preferably, the pharmaceutical composition according to the present invention can be applied in the form of a solution, e.g. for use as an injectable formulation.

Preferably, the pharmaceutical composition according to the invention, preferably for use as an injection preparation, is prepared by mixing sugammadex or a salt thereof, preferably sugammadex sodium, with water for injection. Preferably, the water for injection contains less than 100 ppm oxygen, preferably less than 10 ppm oxygen, more preferably less than 1 ppm oxygen. Water for injection containing less than 100 ppm oxygen, preferably less than 10 ppm oxygen, more preferably less than 1 ppm oxygen, can be prepared by bubbling water with an inert gas. The inert gas may be nitrogen or argon, preferably nitrogen.

The solution formed during the process of mixing sugammadex or a salt thereof, preferably sugammadex sodium, with water for injection containing less than 100 ppm oxygen, preferably less than 10 ppm oxygen, more preferably less than 1 ppm oxygen, is preferably bubbled with an inert gas, preferably nitrogen. The resulting solution is then preferably filtered and filled into vials. Finally, the vials can be sterilized by steam sterilization when heated in an autoclave, preferably at a temperature of 121°C for 15 minutes, although other temperature and time conditions may be used.

The pharmaceutical compositions according to the present invention are described, for example, in the standard reference work Gennaro et al. , Remington's Pharmaceutical Sciences, (18th ed., Mack Publishing Company, 1990, Part 8: Pharmaceutical Preparations and Their Manufacture; see especially Chapter 84, pp. 1545-1569 for "Parental preparations"; and Chapter 85, pp. 1570-1580 for "Intravenous admixtures"), by mixing sugammadex or a salt thereof, preferably sugammadex sodium, obtained according to the process of the present invention, with a pharma- ceutical suitable liquid and, optionally, with pharma-ceutical suitable auxiliaries. Preferably, the pharmaceutical composition according to the present invention is prepared by mixing sugammadex or a salt thereof, preferably sugammadex sodium, obtained according to the method of the present invention with purified water.

Alternatively, the pharmaceutical compositions of the invention may be presented in single-dose or multi-dose containers, such as sealed vials and ampoules, requiring only the addition of a sterile liquid carrier, such as water, before use. It may be stored in a freeze-dried state.

In a further aspect, the present invention provides for neuromuscular blockade and its reversal, comprising (a) a neuromuscular blocking agent, and (b) sugammadex or a salt thereof, preferably sugammadex sodium, prepared according to the method of the present invention. Regarding the kit.

A preferred kit according to the present invention contains sugammadex or a salt thereof, preferably sugammadex sodium, prepared according to the method of the present invention, and a neuromuscular blocker selected from the group consisting of rocuronium, vecuronium, pancuronium, rapacuronium, mivacurium, atracurium, (cis)atracurium, tubocurarine and suxamethonium.

As used herein, the term "about" preceding and referring to a numerical value is meant to indicate any value within a range defined by a numerical value of ±10% of that value, preferably within a range defined by a numerical value of ±5%, more preferably within a range defined by a numerical value of ±2%, and even more preferably within a range defined by a numerical value of ±1%. For example, "about 10" should be interpreted to mean within a range of 9 to 11, preferably within a range of 9.5 to 10.5, more preferably within a range of 9.8 to 10.2, and even more preferably within a range of 9.9 to 10.1.

The following examples further illustrate the invention but, of course, should not be construed as limiting its scope in any way.

General experimental conditions:
HPLC Method Used for 6-Per-deoxy-6-per-chloro-γ-cyclodextrin (Compound II-A) Chromatographic separation was performed at 30° C. using an Inertsil C8-3, 5 μm, 4.6×250 mm.

The mobile phase was a gradient grade 0.08% v/v trifluoroacetic acid solution in water/acetonitrile (50:50) v/v.

The chromatogram was run for 30 minutes.

The chromatograph was equipped with an ELSD or CAD detector. The flow rate was 1.0 mL/min.

The test sample had a concentration of 1 mg/mL and was prepared, for example, by dissolving 20 mg of the sample in methanol in a 20 mL volumetric flask.

HPLC Method Used for Monosodium Salt of 3-Mercaptopropionic Acid (Formula IV-A) Chromatographic separation was performed at 20-25°C using an Atlantis T3, 5 μm, 4.6×250 mm.

Mobile phase A was 10 mM phosphate buffer, pH 2.5.

Mobile phase B was gradient grade acetonitrile.

The chromatograph was programmed as follows: first 10 minutes isocratic 95% mobile phase A; linear gradient 10-25 minutes to 80% phase A; 25-45 minutes isocratic 80% phase A; Linear gradient to 95% Phase A in 45-50 minutes; isocratic 95% Phase A in 50-60 minutes.

The chromatograph was equipped with a UV Waters 2487 detector (210 nm). The flow rate was 1.0 mL/min.

The sample has a concentration of 15 mg/mL, for example by dissolving 150 mg in 10 mL of diluent (diluent: 1.0% v/v HCl solution in water/acetonitrile (6:4) v/v). Prepared.

HPLC Method Used for Sugammadex Sodium (Compound I) Chromatographic separation was performed at 40° C. using a YMC Pack Pro C18, 3 μm, 4.6×250 mm column.

Mobile phase A was 10 mM phosphate buffer at pH 2.

Mobile phase B was a gradient grade methanol/acetonitrile (95:5) v/v mixture.

The chromatograph was programmed as follows: isocratic 65% mobile phase A in the first 4 min; linear gradient 4-8 min to 60% phase A; isocratic 60% phase A in 8-27 min; linear gradient 27-85 min to 50% phase A; isocratic 50% phase A in 85-90 min; linear gradient 90-95 min to 65% phase A; isocratic 65% phase A in 95-105 min.

The chromatograph was equipped with a UV Waters 2487 detector (210 nm). The flow rate was 0.95 mL/min.

The sample had a concentration of 8 mg/mL and was prepared, for example, by dissolving 80 mg in 10 mL of diluent (diluent: water/methanol (9:1) v/v).

X-ray Powder Diffraction (XRPD):
XRPD patterns were recorded on a Siemens D5000 diffractometer equipped with two symmetrically mounted vertical goniometers (Bragg-Brentano geometry) with a horizontal sample stage, an X-ray tube, a high voltage generator (operated at 45 kV and 35 mA), and a standard scintillation detector. A Ni-filtered Cu anode source was used, and the diffracted radiation was further monochromated with a graphite crystal to avoid fluorescence effects [lambda(Kα)=1.54056 Å]. Diffraction patterns were recorded including 2θ values ranging from 2 to 50° at a sampling rate of 0.02° per second, with a step time of 1 s per step. Powdered samples were pressed between two glass plates to form a film. Data were recorded and primary analysis of the diffraction patterns was performed using DIFFRAC Plus measurement software with EVA evaluation software (Bruker). The instrument was routinely calibrated using quartz and silicon.

Example 1: Preparation of 6-per-deoxy-6-per-chloro-γ-cyclodextrin (Compound II-A) 24.0 g of γ-cyclodextrin (water content less than 0.5%) and 13.5 g of lithium chloride (314.5 mmol) was dissolved in 840 mL of N,N-dimethylformamide at 20-25° C. under nitrogen atmosphere. 24.4 mL of methanesulfonyl chloride was added and the resulting mixture was heated to 60-70° C. and stirred at this temperature until the reaction was complete. The mixture was cooled to 25°C. The resulting mixture was diluted with acetone and basified to pH 8 with aqueous sodium hydroxide. The solid was isolated by filtration and washed with acetone. HPLC purity: 98.1%. The crude solid was suspended in a mixture of 50 mL methanol, 125 mL acetone, and 125 mL deionized water. The resulting suspension was filtered and the solid was washed with acetone and dried under vacuum to constant weight to yield 20 g of 6-per-deoxy-6-per-chloro-γ-cyclodextrin. . Yield: 75%. Purity (HPLC): 99.5%.

Example 2: Preparation of 6-per-deoxy-6-per-chloro-γ-cyclodextrin (Compound II-A) 29.0 kg of dry γ-cyclodextrin (water content less than 0.5%) and 16.2 kg of lithium chloride were dissolved in 1014 L of N,N-dimethylformamide at 20-25° C. under nitrogen atmosphere. 60.5 kg of methanesulfonyl chloride was added and the resulting mixture was heated to 60-70° C. and stirred at this temperature until the reaction was complete. The mixture was cooled to 25° C. The resulting mixture was diluted with acetone and basified to a pH greater than 12 with aqueous sodium hydroxide. The mixture was then cooled to −10° C. and the pH was brought to 8.5 with aqueous hydrochloric acid and filtered. The mixture was suspended in a mixture of 58 L of methanol and 145 L of water and the pH was brought to less than 1.0 with aqueous hydrochloric acid. The mixture was heated at 50° C. for 5 hours, then cooled to 20-25° C. and 145 L of acetone was added. The mixture was cooled to -10°C and filtered. The solid was suspended in 58 L of methanol. 145 L of water was added and the pH was adjusted to 8.5 with sodium hydroxide. 145 L of acetone was added. The mixture was cooled to -10°C, filtered and dried. Yield: 70.9%.

Example 3: Preparation of 6-per-deoxy-6-per-chloro-γ-cyclodextrin (Compound II-A) 5.0 g of dry γ-cyclodextrin was dissolved in 175 mL of N,N-dimethylformamide at room temperature under nitrogen. After dissolution, 5.09 mL of methanesulfonyl chloride was added. The reaction mixture was heated to 65° C. and stirred until the reaction was complete. The mixture was cooled to 20-25° C. and 100 mL of acetone was added followed by 100 mL of water. 8 mL of NaOH 50% w/v was added dropwise and then HCl 5M was added to the above suspension until pH=8. The resulting slurry was stirred at room temperature for 30 minutes and filtered. The resulting solid was washed with acetone and dried under vacuum to constant weight to obtain crude 6-per-deoxy-6-per-chloro-γ-cyclodextrin. Purity (HPLC): 94.0%.

Example 4: Preparation of monosodium salt of 3-mercaptopropionic acid (compound IV-A) 50 g (471.08 mmol) of 3-mercaptopropionic acid was dissolved in 200 mL of isopropanol. The resulting solution was stirred for at least 10 minutes at 20-25°C. 19 g of sodium hydroxide solid (granules) were added at 20-30°C. The resulting suspension was stirred at 20-25°C for 2 hours. Then 25 mL of n-heptane was added and the suspension was cooled to 5-10°C. After stirring this for 1 hour to 5-10°C, the precipitated solid was filtered, washed with n-heptane and dried under vacuum at 60-65°C for a minimum of 4 hours to yield 48.3g of the title compound. I got it. Yield: 80%. Purity (HPLC): 98.68%.

Example 5: Preparation of monosodium salt of 3-mercaptopropionic acid (compound IV-A) 90 g (847.94 mmol) of 3-mercaptopropionic acid was dissolved in 360 mL of isopropanol. The resulting solution was stirred for at least 10 minutes at 20-25°C. 32.5 g of sodium hydroxide solid (granules) were added at 20-30°C. The resulting suspension was stirred at 20-25°C for 2 hours. Then 44 mL of n-heptane was added and the suspension was cooled to 5-10°C. After stirring this for 1 hour to 5-10°C, the precipitated solid was filtered, washed with n-heptane and dried under vacuum at 60-65°C for a minimum of 4 hours to yield 82.6g of the title compound. I got it. Yield: 76%. Purity (HPLC): 97.60%.

Example 6: Isolation of monosodium salt of 3-mercaptopropionic acid (Compound IV-A) Preparation of Sugammadex sodium (Compound I) A round bottom flask was charged with 14.19 g of monosodium salt of 3-mercaptopropionic acid prepared according to Example 4, 120 mL of N,N-dimethylformamide and 30 mL of methanol. A solution of 10 g of 6-per-deoxy-6-per-chloro-γ-cyclodextrin prepared according to Example 1 in 80 mL of N,N-dimethylformamide was added to the above solution at 20-25° C. under nitrogen. After stirring for 15 minutes, 4.43 g of NaOH (granular) was added in portions at 20-25° C. under nitrogen. The resulting mixture was stirred at 20-30° C. for 1 hour. The resulting suspension was stirred at 95-100° C. for 6 hours followed by 10 hours at 105-110° C. After cooling to 20-25°C, 50 mL of water and 100 mL of methanol were added and the pH was adjusted to 8±0.5 by adding hydrochloric acid 4-5 M. The precipitated solid was collected by filtration and washed with methanol. Purity (HPLC): 95.14%.

Example 7: Purification of Sugammadex Sodium (Compound I) Sugammadex sodium obtained in Example 6 was dissolved in 30 mL of deionized water and precipitated by adding 200 mL of methanol under nitrogen at 20-25° C. The resulting suspension was filtered and washed with methanol to obtain a wet solid. Purity (HPLC): 95.57%.

The resulting solid was dissolved in 30 mL of deionized water and precipitated by adding 200 mL of methanol at 20-25° C. under nitrogen. The resulting suspension was filtered and washed with methanol to yield 13.58 g of wet solid. Purity (HPLC): 97.70%.

13.58 g of wet sugammadex sodium was dissolved in 30 mL of deionized water at 20-25° C. under nitrogen. After dissolution, the pH was adjusted to 9.75±0.25 by adding 1M sodium hydroxide. A solution of 24.1 mg of methyl acrylate in 5.59 mL of methanol was slowly added to the above solution, maintaining the temperature at 20-25°C. The resulting solution was stirred at 20-25°C for 2 hours. After the reaction was completed, 30 mL of n-heptane was added and the resulting biphasic solution was stirred at 20-25° C. for 2 hours. Then, 170 mL of methanol was added. The resulting precipitate was stirred at 20-25° C. for 1 hour, filtered and washed with methanol, yielding 10.36 g of wet Sugammadex solid. Purity (HPLC): 98.42%.

The resulting wet solid was dissolved in 45 mL of deionized water at 20-25° C. under nitrogen. After dissolution, the pH was adjusted to 11.75±0.25 by adding 1M sodium hydroxide. The resulting solution was stirred at 20-25° C. for 4 hours, filtered, and washed with 5 mL of deionized water to obtain a clear solution. The filtrate was stirred at 20-25° C. and 10 mL of ethanol was added to the filtrate. The resulting solution was slowly added to 50 mL of ethanol, followed by 100 mL of ethanol at 20-25°C. The contents were stirred at the same temperature for 1 hour, filtered, washed with ethanol, and dried under vacuum at 70-75° C. to yield 7.38 g of sugammadex sodium. Purity (HPLC): 99.28%. Powder X-ray diffraction: See Table 1 and Figure 3.

Example 8: Preparation of Sugammadex Sodium (Compound I) to Isolate the Monosodium Salt of 3-Mercaptopropionic Acid (Compound IV-A) A reactor was charged with the monosodium salt of 3-mercaptopropionic acid prepared according to Example 5. 1.42 kg, 12 L of N,N-dimethylformamide and 3 L of methanol were charged. A solution of 1 kg of 6-per-deoxy-6-per-chloro-γ-cyclodextrin prepared according to Example 1 in 8 L of N,N-dimethylformamide was added to the above solution at 20-25° C. under nitrogen. was added. After stirring for 15 minutes, 440 g of NaOH (granules) were added in portions at 20-25° C. under nitrogen. The resulting mixture was stirred at 20-30°C for 1 hour. The resulting suspension was stirred at 95-100°C for 6 hours and then at 105-110°C for 10 hours. After cooling to 20-25° C., 5 L of water and 10 L of methanol were added, and the pH was adjusted to 8±0.5 by adding 5 M hydrochloric acid. The precipitated solid was collected by filtration and washed with methanol. Purity (HPLC): 95.9%.

Example 9: Purification of Sugammadex Sodium (Compound I) Sugammadex sodium obtained in Example 8 was dissolved in 3 L of deionized water and precipitated by adding 19.8 L of methanol under nitrogen at 20-25°C. Ta. The resulting suspension was filtered and washed with methanol to obtain a wet solid.

The resulting solid was dissolved in 3 L of deionized water and precipitated by adding 19.8 L of methanol under nitrogen at 20-25°C. The resulting suspension was filtered and washed with methanol to obtain a wet solid.

The resulting wet sugammadex sodium was dissolved in 3 L of deionized water at 20-25° C. under nitrogen. After dissolution, the pH was adjusted to 9.75±0.25 by adding 4M sodium hydroxide. A solution of 2.4 g of methyl acrylate in 0.56 L of methanol was slowly added to the above solution, maintaining the temperature at 20-25°C. The resulting solution was stirred at 20-25°C for 4 hours. After the reaction was completed, 3L of n-heptane was added and the resulting mixture was stirred at 20-25°C for 2 hours. Then, 17 L of methanol was slowly added. The resulting precipitate was stirred at 20-25° C. for 1 hour, filtered, and washed with methanol to obtain wet sugammadex sodium solid.

The resulting wet solid was dissolved in 4.5 L of deionized water at 25-30° C. under nitrogen. After dissolution, the pH was adjusted to 11.75±0.25 by adding sodium hydroxide. The resulting solution was stirred at 25-30°C for 4 hours. The pH was then adjusted to 9.25±0.25 at 25-30°C by adding hydrochloric acid. The solution was filtered and washed with 0.5 L of deionized water to obtain a clear solution. The filtrate was stirred at 20-25°C and 1 L of ethanol was added to the filtrate. The resulting solution was slowly added to 5 L of ethanol, followed by the addition of 1 L of ethanol at 20-25°C. The contents were stirred at the same temperature for 1 hour, filtered, washed with ethanol, and dried under vacuum at 70-75° C. to yield 0.867 kg of sugammadex sodium. Purity (HPLC): 98.90%.

Example 10: Determination of the hygroscopic properties of the monosodium salt of 3-mercaptopropionic acid (compound IV-A) and the disodium salt of 3-mercaptopropionic acid (compound V-A) obtained according to WO 2017/163165A1 Comparative Study Monosodium 3-mercaptopropionic acid (compound IV-A) obtained as disclosed in Example 4 or 5 and 3-mercaptopropionic acid obtained according to WO 2017/163165A1 The hygroscopicity of both disodium salts (compound (VA)) was determined according to the European Pharmacopoeia 5.0 hygroscopicity method, which is used to provide an indication of the degree of hygroscopicity of the sample.

A glass weighing container and a stopper having an outer diameter of 50 mm and a height of 15 mm were weighed (m1). The sample to be tested was placed in a container and the stoppered container containing the sample was weighed (m2). The unstoppered container containing the sample was placed in a 25° C. desiccator containing a saturated solution of ammonium chloride to maintain a relative humidity of 80±2%. The stoppered weighing vessels containing the samples were weighed at various times (m3).

The weight gain of each sample at a specific time was calculated using the following formula:
(m3-m2)/(m2-m1)×100

Table 2 shows the results obtained for each salt.

The results show that the monosodium salt of 3-mercaptopropionic acid (compound IV-A) and the di-sodium salt of 3-mercaptopropionic acid during the hydration process at 25° C. and 80 ± 2% relative humidity (RH) immediately after drying. It is presented in Figure 4 showing the weight gain rate of the sodium salt (Compound VA). Lower weight gain at the same relative humidity means less risk of introducing excessive amounts of uncontrolled water during handling. Therefore, monosodium salts are preferred for this reaction.

The data show that the monosodium salt (Compound IV-A) is less hygroscopic than the disodium salt (Compound VA).

All references cited herein, including publications, patent applications, and patents, are hereby incorporated by reference to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and set forth in its entirety herein.

In the context of the present description (particularly in the context of the claims below), the use of the terms "a" and "an" as well as "the" and "at least one" and similar referents should be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of the term "at least one" followed by a list of one or more items (e.g., "at least one of A and B") is to be construed to mean one item selected from the enumerated item (A or B), or any combination of two or more of the enumerated items (A or B), unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to"), unless otherwise indicated. As used herein, unless otherwise indicated herein, the recitation of ranges of values is merely intended to serve as a shorthand method of referring individually to each separate value within the range, and each separate value is incorporated herein as if each separate value were individually recited herein. All methods described herein may be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. Any examples provided herein, or the use of example language (e.g., "such as"), are intended merely to facilitate illustration of the invention and do not limit the scope of the invention unless otherwise specified. No language in this specification should be construed as indicating any element not recited in the claims as essential to the practice of the invention.

Preferred embodiments of the invention, including the best mode for carrying out the invention known to the inventors, are described herein. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the above description. The inventors anticipate that those of ordinary skill in the art will employ such variations as appropriate, and the inventors contemplate the invention being practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims (13)

A process for preparing sugammadex sodium, comprising the steps of:
a) reacting 3-mercaptopropionic acid of formula (III) in an alcohol solvent

with a sodium ionic base to obtain the monosodium salt of formula (IV-A);

b) isolating the monosodium salt of formula (IV-A);
c) reacting the monosodium salt of formula (IV-A) isolated in step b) with a compound of formula (II-A) or a hydrate or solvate thereof in a mixture of a polar aprotic solvent selected from the group consisting of dimethylsulfoxide , N,N-dimethylacetamide and N,N-dimethylformamide and an alcoholic solvent selected from the group consisting of methanol, ethanol, n-propanol, isopropanol and n - butanol in the presence of sodium hydroxide;

The method according to claim 1, further comprising: The monosodium salt of the formula (IV-A) has two theta (2θ): 6.1, 6.6, 24.9, 27.6, 30.2, 30.7 and 37.7±0.2. 2. A method according to claim 1, characterized in that it has an X-ray powder diffraction (XRPD) pattern comprising a peak at . The method according to claim 1 or 2, wherein the sodium ionic base of step a ) is selected from the group comprising sodium amide, sodium hydride, sodium alkoxide, sodium hydroxide and/or mixtures thereof. . 4. The method of claim 3, wherein the sodium ionic base in step a ) and the sodium hydroxide in step c) are sodium hydroxide in solid form. 5. A method according to any one of claims 1 to 4, wherein step a) is carried out in an alcoholic solvent selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol and mixtures thereof. Method. Process according to claim 5, wherein step a) is carried out in isopropanol and step c) is carried out in a mixture of N,N-dimethylformamide and methanol. A method according to any one of claims 1 to 6, wherein step c) is carried out at a temperature of 95°C to 110°C. A method according to claim 7, wherein step c) is carried out at 95-100°C for 4-8 hours, followed by 105-110°C for 8-12 hours. The compound of formula (II-A) or its hydrate or solvate is
d ) reacting a sulfonyl chloride with a tertiary amide compound to form a Vilsmeier reagent;
e ) reacting the Vilsmeier reagent with γ-cyclodextrin . 10. The method of claim 9 , wherein the sulfonyl chloride is methanesulfonyl chloride and the tertiary amide compound is N,N-dimethylformamide. 11. The method according to claim 9 or 10, wherein the reaction of the Vilsmeier reagent with γ-cyclodextrin in step e ) is carried out in the presence of a halide salt, said halide salt being a chloride salt selected from the group comprising lithium chloride, sodium chloride, potassium chloride, cesium chloride, magnesium chloride, calcium chloride, quaternary ammonium chlorides, and / or mixtures thereof. 12. The method of claim 11 , wherein the chloride salt is lithium chloride. 13. The method according to any one of claims 1 to 12 , further comprising a purification step of sugammadex sodium by recrystallization or suspension in a mixture of water, methanol or ethanol, and optionally heptane.

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